The present invention relates to a solid, controlled-release oral dosage form for use in the treatment of pain.
It is the intent of all controlled (slow) release formulations to provide a longer period of pharmacologic action after administration than is ordinarily obtained after administration of immediate-release dosage forms. Such longer periods of response provide for many therapeutic benefits that are not achieved with corresponding short acting, immediate release preparations. Thus, therapy may be continued without interrupting the sleep of the patient, which is of special importance, for example, when treating a patient for moderate to severe pain (e.g., a post-surgery patient, a cancer patient, etc.), or for those patients who experience migraine headaches on awakening, as well as for the debilitated patient for whom sleep is essential.
Unless conventional rapid acting drug therapy is carefully administered at frequent intervals to maintain effective steady state blood levels of the drug, peaks and valleys in the blood level of the active drug occurs because of the rapid absorption, systemic excretion of the compound and through metabolic in-activation, thereby producing special problems in maintenance therapy of the patient. A further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through patient forgetfulness.
Morphine, which is considered to be the prototypic opioid analgesic, has been formulated into 12 hour controlled-release formulations (i.e., MS Contin® tablets, commercially available from Purdue Frederick Company).
It has previously been known in the art that controlled-release compositions of opioids or salts thereof could be prepared in a suitable matrix. For example, in U.S. Pat. Nos. 4,990,341 and 4,844,909 (Goldie, et al.), both assigned to the assignee of the present invention, describes hydromorphone compositions wherein the dissolution rate in-vitro of the dosage form, when measured by the USP Paddle or Basket Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C., is between 12.5 and 42.5% (by wt) hydromorphone released after 1 hour, between 25 and 55% (by wt) released after 2 hours, between 45 and 75% (by wt) released after 4 hours and between 55 and 85% (by wt) released after 6 hours, the in-vitro release rate being independent of pH between pH 1.6 and 7.2 and chosen such that the peak plasma level of hydromorphone obtained in-vivo occurs between 2 and 4 hours after administration of the dosage form. At least 12 hours of pain relief is obtained with these hydromorphone formulations.
It has been a further goal in the art to develop drug formulations which provide a duration of effect longer than 12 hours, so that, for example, the drug may be administered to the patient only once a day.
There is clearly a need for convenient and reliable dosage formulations of opioid analgesics that can be administered less frequently than currently available such drugs. Most currently available such oral opioid analgesic formulations need to be administered every four to six hours with only a selected few formulated for less frequent 12 hour dosing. The obvious advantages for once daily dosing formulations would be both increased convenience and compliance, as have been documented for numerous medication formulations when the requirement for less frequent dosing is provided.
To date, it has not been the consensus that the formulation of oral opioid analgesics in a way that provides for less frequent dosing either (a) has any influence on the profile and/or incidence of adverse drug reactions as compared to the same chemical entity administered in conventional immediate-release oral formulations at the same total daily dose or (b) that there are any differences in the analgesic efficacy of longer as compared to shorter acting oral opioid analgesic formulations in terms of the dosage required over given periods of time. The results of numerous adequate and well-controlled double-blind, randomized, safety and efficacy evaluations demonstrate comparable profiles, incidences and intensities of opioid side effects and comparable analgesia at equal daily dosages of long- and shorter-acting oral opioids as evidenced from the results of numerous such studies.
While the concurrent administration of non-opioid analgesic drugs along with opioid drugs have provided for evidence of the “opioid-sparing” effect of non-opioid analgesics, the only previously reported method of decreasing opioid requirements have been in the situation where patient-controlled analgesia (PCA) reduces the need for opioid analgesics as compared to when administered as-needed (PRN), both via parenteral routes. In these latter situations, neither method of administration is at fixed intervals but, rather, PRN, with the patient as the primary controller of drug administration utilizing PCA and both the patient and another party, who controls the timing of as-needed but PRN medication in the usual fashion.
It is an object of the present invention to provide a method and opioid analgesic formulation for substantially improving the efficiency and quality of pain management.
It is another object of the present invention to provide a method of treatment for substantially improving the efficiency and quality of pain management.
It is yet another object of the present invention to provide controlled-release opioid formulations which have a substantially increased duration of effect as compared to previously known controlled-release opioid formulations.